Methods of treating heart failure with cardiac sarcomere activators

Abstract

Provided herein are methods of treating a subject with heart failure, comprising administering to the subject an initial dose of a cardiac sarcomere activator (CSA) for an initial time period, and subsequently administering to the subject a dose of the CSA based on the subject's plasma concentration of the CSA at the end of the initial time period.

What is claimed is: 
     
       1. A method of determining a treatment regimen for a subject with heart failure (HF), comprising
 (a) administering to the subject an initial dose of a cardiac sarcomere activator (CSA) for an initial time period, wherein the initial dose of the CSA is about 25 mg twice daily, 
 (b) determining the subject's plasma concentration of the CSA at about 2 weeks after the first administration of the initial dose, and 
 (c) determining a treatment regimen based on the subject's plasma concentration of the CSA, 
 wherein the treatment regimen comprises (i) administering to the subject an initial dose of the CSA for an initial time period, wherein the initial dose of the CSA is about 25 mg twice daily; and (ii) subsequently administering to the subject a dose of the CSA for a second time period based on the subject's plasma concentration of the CSA at about 2 weeks after the first administration of the initial dose, 
 wherein when the subject's plasma concentration of the CSA is less than a threshold concentration of 300 ng/mL, the dose subsequently administered to the subject is greater than the initial dose; and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. The method of  claim 1 , wherein the dose subsequently administered to the subject is a maximum dose. 
     
     
       3. The method of  claim 2 , wherein the maximum dose is about 50 mg twice daily. 
     
     
       4. The method of  claim 1 , wherein the dose subsequently administered to the subject is about 50 mg twice daily. 
     
     
       5. The method of  claim 1 , wherein the dose subsequently administered to the subject is about 37.5 mg twice daily. 
     
     
       6. The method of  claim 1 , wherein the dose subsequently administered to the subject is about 25 mg twice daily. 
     
     
       7. The method of  claim 1 , wherein the CSA is omecamtiv mecarbil dihydrochloride hydrate. 
     
     
       8. The method of  claim 1 , wherein the treatment regimen is effective to achieve a target plasma concentration of about 300 ng/mL to about 750 ng/mL. 
     
     
       9. The method of  claim 1 , wherein the initial time period is about 3 weeks. 
     
     
       10. The method of  claim 1 , wherein the initial time period is at least about 2 weeks. 
     
     
       11. The method of  claim 1 , wherein the initial time period is about 4 weeks. 
     
     
       12. The method of  claim 1 , wherein when the subject's plasma concentration of the CSA is greater than or equal to a minimum of a target concentration range, the dose subsequently administered to the subject is the same as the initial dose. 
     
     
       13. The method of  claim 12 , wherein the minimum of the target concentration range is 300 ng/mL. 
     
     
       14. The method of  claim 1 , wherein the method further comprises administering to the subject a third dose of the CSA for a third time period that follows the second time period based on the subject's second plasma concentration of the CSA. 
     
     
       15. The method of  claim 14 , wherein the subject's second plasma concentration of the CSA is measured at about 6 weeks after the first administration of the initial dose. 
     
     
       16. The method of  claim 14 , wherein the second time period is at least about 2 weeks. 
     
     
       17. The method of  claim 14 , wherein the third dose of the CSA is the same as the second dose when the subject's second plasma concentration of the CSA is less than about 750 ng/ml. 
     
     
       18. The method of  claim 14 , wherein the third dose of the CSA is less than the second dose when the subject's second plasma concentration of the CSA is greater than or about 1000 ng/ml. 
     
     
       19. The method of  claim 14 , wherein the third dose of the CSA is the same as or less than the second dose when the subject's second plasma concentration of the CSA is greater than or about 750 ng/mL but less than 1000 ng/mL. 
     
     
       20. The method of  claim 14 , wherein the third dose is about 25 mg twice daily. 
     
     
       21. The method of  claim 14 , wherein the third dose is about 37.5 mg twice daily. 
     
     
       22. The method of  claim 14 , wherein the third dose is about 50 mg twice daily. 
     
     
       23. The method of  claim 14 , wherein the third dose of the CSA is less than the second dose. 
     
     
       24. The method of  claim 14 , wherein the third dose of the CSA is greater than the second dose. 
     
     
       25. The method of  claim 14 , wherein the third dose of the CSA is the same as the second dose. 
     
     
       26. The method of  claim 1 , wherein the subject has chronic heart failure, or a New York Heart Association Class II or III heart failure. 
     
     
       27. The method of  claim 1 , wherein the subject has a left ventricular ejection fraction of about 40% or lower. 
     
     
       28. The method of  claim 1 , wherein the subject has a plasma concentration of NT-proBNP of at least about 200 μg/mL. 
     
     
       29. The method of  claim 1 , wherein the CSA is administered orally to the subject. 
     
     
       30. A method of determining a treatment regimen for a subject with heart failure (HF), comprising
 (a) administering to the subject an initial dose of a cardiac sarcomere activator (CSA) of 25 mg twice daily for an initial time period, 
 (b) determining the subject's plasma concentration of the CSA at about 2 weeks after the first administration of the initial dose, and 
 (c) determining a treatment regimen based on the subject's plasma concentration of the CSA, 
 wherein the treatment regimen comprises (i) administering to the subject an initial dose of the CSA of about 25 mg twice daily for an initial time period; and (ii) subsequently administering to the subject a dose of the CSA for a second time period based on the subject's plasma concentration of the CSA measured at about 2 weeks after the first administration of the initial dose, 
 wherein the dose subsequently administered to the subject is (ii-a) about 25 mg twice daily, when the subject's plasma concentration of the CSA is greater than or about 300 ng/mL; (ii-b) about 37.5 mg twice daily, when the subject's plasma concentration of the CSA is greater than or about 200 ng/mL but less than 300 ng/mL; or (ii-c) about 50 mg twice daily, when the subject's plasma concentration of the CSA is less than 200 ng/ML; and wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt thereof. 
 
     
     
       31. A method of determining a treatment regimen for a subject with heart failure (HF), comprising
 (a) administering to the subject an initial dose of a cardiac sarcomere activator (CSA) of 25 mg twice daily for an initial time period of about 4 weeks, 
 (b) determining the subject's plasma concentration of the CSA at about 2 weeks after the first administration of the initial dose, and 
 (c) determining a treatment regimen based on the subject's plasma concentration of the CSA, 
 wherein the treatment regimen comprises (i) administering to the subject an initial dose of the CSA of about 25 mg twice daily for an initial time period of about 4 weeks; and (ii) subsequently administering to the subject a dose of the CSA for a second time period based on the subject's plasma concentration of the CSA measured at about 2 weeks after the first administration of the initial dose, 
 wherein the dose subsequently administered to the subject is (ii-a) about 25 mg twice daily, when the subject's plasma concentration of the CSA is greater than or about 300 ng/mL; (ii-b) about 37.5 mg twice daily, when the subject's plasma concentration of the CSA is greater than or about 200 ng/mL but less than 300 ng/mL; or (ii-c) about 50 mg twice daily, when the subject's plasma concentration of the CSA is less than 200 ng/mL; wherein the CSA is omecamtiv mecarbil, or a pharmaceutically acceptable salt thereof; and wherein the CSA is orally administered to the subject.